Low Caspofungin Exposure in Patients in Intensive Care Units

Abstract

In critically ill patients, drug exposure may be influenced by altered drug distribution and clearance. Earlier studies showed that the variability in caspofungin exposure was high in intensive care unit (ICU) patients. The primary objective of this study was to determine if the standard dose of caspofungin resulted in adequate exposure in critically ill patients. A multicenter prospective study in ICU patients with (suspected) invasive candidiasis was conducted in the Netherlands from November 2013 to October 2015. Patients received standard caspofungin treatment, and the exposure was determined on day 3 of treatment. An area under the concentration-time curve from 0 to 24 h (AUC 0 -24 ) of 98 mg · h/liter was considered adequate exposure. In case of low exposure (i.e., Ͻ79 mg · h/liter, a Ն20% lower AUC 0 -24 ), the caspofungin dose was increased and the exposure reevaluated. Twenty patients were included in the study, of whom 5 had a positive blood culture. The median caspofungin AUC 0 -24 at day 3 was 78 mg · h/liter (interquartile range [IQR], 69 to 97 mg · h/liter). A low AUC 0 -24 (Ͻ79 mg · h/liter) was seen in 10 patients. The AUC 0 -24 was significantly and positively correlated with the caspofungin dose in mg/kg/day (P ϭ 0.011). The median AUC 0 -24 with a caspofungin dose of 1 mg/kg was estimated using a pharmacokinetic model and was 114.9 mg · h/liter (IQR, 103.2 to 143.5 mg · h/liter). In conclusion, the caspofungin exposure in ICU patients in this study was low compared with that in healthy volunteers and other (non)critically ill patients, most likely due to a larger volume of distribution. A weight-based dose regimen is probably more suitable for patients with substantially altered drug distribution. (This study has been registered at ClinicalTrials.gov under registration no. NCT01994096.)

Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin Levels

“…As shown in the current study, hyperbilirubinemia and hypoalbuminemia may represent two such counteracting factors. There was a relatively large interindividual variation in the AUC 0 -24 and the other PK parameters, which is in agreement with previous studies on caspofungin pharmacokinetics in ICU patients (14,15,18). The AUC 0-24 values in our patients compared with those observed in these studies and healthy subjects are shown in Table S4 in the supplemental material.…”

“…However, in the case of fluconazole there has been good agreement between human and murine data (24,25). As previously proposed for anidulafungin (17) and caspofungin (18), current data suggest that therapeutic drug monitoring (TDM) is relevant in critically ill In addition to being considerably larger than previous studies, the strength of the present study is its separate analyses of individual components of the C-P score, demonstrating counteracting effects of bilirubin and albumin. Thus, by expanding the knowledge of liver function and how PK parameters are affected in the critically ill, we can make more robust decisions on dosage of caspofungin.…”

Intensive care medicine research agenda on invasive fungal infection in critically ill patients

“…Recent studies showed that echinocandins exposure in ICU patients was low compared with healthy volunteers and other (non-)critically ill patients, most likely as a result of a larger volume of distribution, suggesting that a weight-based dose regimen should probably be more suitable for patients with substantially altered drug distribution [45][46][47].…”

Strategies to Improve Medication Adherence in Older Persons: Consensus Statement from the Senior Italia Federanziani Advisory Board

“…TDM is not recommended for the echinocandins or amphotericin B by the current guidelines, although studies report significant variability in echinocandin exposure in specific patient populations [56,[63][64][65]. Decreased and potentially inadequate echinocandin exposure induced by physiological changes in critically ill patients may result in ineffective treatment and drug resistance [63][64][65].…”

“…Decreased and potentially inadequate echinocandin exposure induced by physiological changes in critically ill patients may result in ineffective treatment and drug resistance [63][64][65]. Although in vitro studies have shown a concentration-effect relationship, a clear relationship between exposure and therapeutic response is currently lacking [60].…”